⭐Manifestations of diabetic neuropathy

• Diffuse neuropathy is probably caused by increased sorbitol and fructose in the Schwann cells.

1. Earliest is ⭐loss of vibration sense and pain (deep before superficial) and temperature
2. ⭐Later - loss of proprioception.
   2. ⭐Small muscle wasting is also seen in the hands
3. Can present with ⭐IMPROVEMENT of glycaemic control but remits with continue glycaemic control

• Sudden painless palsy of any nerve.
• However, most commonly affects ⭐CN 3 and CN 6;
• Asymmetrical ⭐Pain and weakness of the proximal leg muscles
• Usually asymmetrical.
• Weakened / absent knee reflexes.
• But also ⭐Extensor plantar responses +
  
• Gastrointestinal : vagal damage -> intractable vomiting;

Phase I - double digits (<100)
Phase II - Triple digits (<300)
Phase III - quadruple digits, also C being the 3rd letter of the alphabet, phase III trials 'compare' efficacy -> RCTs. (<3000)
3. Phamacokinetic testing to determine ADME characteristics (absorption, distribution, metabolism and elimination)
Phase 3 = 1000-3000 to confirm effectiveness, monitor side effects and compare with other treatments. (⭐therapeutic confirmation - Randomized controlled trials; efficacy, safety)

[!INFO] Mmemonic: Bag of flowers
⭐

• Isolated systolic hypertension is the predominant form of hypertension in the elderly population.
• develops as a result of the reduced elasticity of the arterial system.
• commonly seen among the elderly as there is increased deposition of calcium and collagen to the arterial wall

• most common cause of blindness in young men
  ++ /dev/null

- **Tau protein** is a protein which stabilizes microtubules and regulates protein binding to microtubules in healthy cells. 

[!INFO] Tau causes Tangles; APP causes Plaques

• Reprogramming of stem cells to differentiate into a cell type that is more suitable to cope with the new stresses than the original cell type at that location. Can occur in epithileal OR mesenchyal cells.
  ⭐
  
• Disorderly, but non neoplastic proliferation.

Other causes of subtotal villous atrophy

• CVID can also cause SVA.

• Cyst is the infective stage. (Cysts are immediately infectious upon excretion, they can survive chlorinated water)
• Cyst are ingested via contaminated water or food (like salads). Faeco-oral person to person transmission can occur (eg. Child care centers)
• Abdominal pain, watery diarrhea, weight loss.
• Severe infection can invade the mucosa in severe infection but usually there is no invasion.
• Treatment: tinidazol, ⭐metronidazole is second line due to concern of side effects. Achieves parasite clearance within 1 week.

1. AL amyloidosis <- The most common form.
   Other types of amyloidosis:

• See Source
• One example : Dialysis related amyloidosis -> (Aβ2M) Dialysis-related amyloidosis; the precursor proteins is β-2 microglobulin.

[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.

[!INFO] Once the presense of amyloid is found

the precursor protein must be determined.
(Both (AL and AA) have the beta pleted sheet structure) (Harrison's - page 804)

[!INFO] AL Amyloidosis and mutliple myeloma are closely related but NOT the same.

• In AL amyloidosis, free light chains are secreted in excess by a small plasma cell clone population in the bone marrow without evidence of multiple myeloma (in AL amyloidosis, there are <10% malignant plasma cells in bone marrow) Source
• To diagnose multiple myeloma >10% of bone marrow aspirate cells should be plasma cells. Source
• 10% of myeloma patients of multiple myeloma patients (mostly those who produced lambda light chains)

• Most frequent sites of AL deposition are the kidneys, heart, peripheral nerves, gastrointestinal tract, and liver
• 

Muscle excitation contraction and neuromuscular junction

Source

[!INFO] What is calcium induced calcium release?
CICR is considered to be the physiological mechanism of Ca2+ release in cardiac muscle. It is generally agreed that an influx of Ca2+ through L-type voltage-dependent Ca2+ channels on the surface and the t-tubule membrane of myocytes activated by an action potential triggers Ca2+ release from the SR by the CICR mechanism to cause cardiac contraction (13, 20, 62, 226, 252). In skeletal muscle where CICR was first discovered, however, the primary mechanism of physiological Ca2+ release is not CICR, but direct protein-protein interaction between the voltage sensor of the t-tubule membrane, the dihydropyridine receptor (DHPR), and the Ca2+ release channel of the SR membrane, the ryanodine receptor (RyR). Source

Even in normal physiology, during repetitive nerve impulses there is a progressive depletion of stored acetylcholine (ACh), causing a decreased number of quanta released from each impulse resulting in a reduction in amplitude of the endplate potentials. (but it remains above the threshold required to elicit a muscle action potential)Source

⭐

Source
Pharmacological efficacy (also called Intrinsic efficacy) is

[[2018-OCT-BSQ#Pulmonary vascular resistance]]

• But ⭐80% of NALFD patients have normal liver enzymes. Source

Pathophysiology of NAFLD

Insulin resistance is the key prerequisite for NAFLD.

• ⭐Steatosis (fatty change), Hepatitis (inflammation) and Fibrosis
• Starts with fat accumulation in centrilobular areas and then spreads outwards. The liver will be soft, yellow and greasy. (i.e starts in ZONE 3)
• Steatosis is ⭐macrovessicular.
  ⭐!
• Hepatocyte ballooning with necrosis
• Intracellular eosinophilic includions: ⭐Mallory Denk bodies
• 
• ⭐Neutrophil infiltration to remove the necrotic hepatocytes and those with Mallory Denk bodies.
  Fibrosis
  ⭐
• Also appears in zone 3 and spread outwards. (⭐central vein sclerosis)
• Perisinusoidal scarring in space of disse also similarly spreads outwards. [[HepaticSinusoidSpaceOfDisse.jpg]]
• These changes cause ⭐micronodular cirrhosis. (aka Laennec cirrhosis)
• Mild increases in ALT and AST with ALT > AST; mild elevation of ⭐gamma-GT. (don't be mislead into thinking it's alcoholic hepatitis)
• Elastography - to evaluate degree of fibrosis.
• Absolute mainstay of treatment: Lifestyle advice aimed at weight loss with exercise and dieting.
• Orlistat (enteric lipase inhibitor) is used as adjunct in severely obese to reduce intestinal lipid absorption
  • Can cause vitamin malabsorption.
  • Pioglitazone has been proven to reduce NASH but weight gain CCF, bladder cancer and fracture risk are increased.
    Source

4. Dyslipidaemia (Low HDL and high TGL)